Inhibition of the mitochondrial pyruvate carrier in astrocytes reduces amyloid and tau accumulation in the 3xTgAD mouse model of Alzheimer's disease.

Alzheimer's Disease (AD) is characterized by an accumulation of pathologic amyloid-beta (Aβ) and Tau proteins, neuroinflammation, metabolic changes and neuronal death. Reactive astrocytes participate in these pathophysiological processes by releasing pro-inflammatory molecules and recruiting the immune system, which further reinforces inflammation and contributes to neuronal death. Besides these neurotoxic effects, astrocytes can protect neurons by providing them with high amounts of lactate as energy fuel.

Preferential Involvement of BRCA1/BARD1, Not Tip60/Fe65, in DNA Double-Strand Break Repair in Presenilin-1 P117L Alzheimer Models.

Recently, we showed that DNA double-strand breaks (DSBs) are increased by the A -amyloid peptide and decreased by all-trans retinoic acid (RA) in SH-SY5Y cells and C57BL/6J mice. The present work was aimed at investigating DSBs in cells and murine models of Alzheimer's disease carrying the mutation. We observed that DSBs could hardly decrease following RA treatment in the mutated cells compared to the wild-type cells.

Neuroprotection against Amyloid--Induced DNA Double-Strand Breaks Is Mediated by Multiple Retinoic Acid-Dependent Pathways.

In this study, we have investigated the role of all--retinoic acid (RA) as a neuroprotective agent against A -induced DNA double-strand breaks (DSBs) in neuronal SH-SY5Y and astrocytic DI TNC cell lines and in murine brain tissues, by single-cell gel electrophoresis. We showed that RA does not only repair A -induced DSBs, as already known, but also prevents their occurrence. This effect is independent of that of other antioxidants studied, such as vitamin C, and appears to be mediated, at least in part, by changes in expression, not of the RAR, but of the PPAR/ and of antiamyloidogenic proteins, such as ADAM10, implying a decreased production of endogenous A.

TSPO and amyloid deposits in sub-regions of the hippocampus in the 3xTgAD mouse model of Alzheimer's disease.

The involvement of the 18kDa translocator protein (TSPO), a marker of neuroinflammation, in Alzheimer's disease (AD) remains controversial. In the present report, we used [I]-CLINDE, a SPECT TSPO radiotracer never before used in AD, and we investigated the relationship between TSPO and amyloid plaque density (using [I]-DRM106) in a triple transgenic mouse model of AD (3xTgAD, APP, PS1 and Tau). Our results show that TSPO increases appear before those of amyloid deposits.

A Study of Aβ Oligomers in the Temporal Cortex and Cerebellum of Patients with Neuropathologically Confirmed Alzheimer's Disease Compared to Aged Controls.

Background/aims: Investigations of Aβ oligomers in neuropathologically confirmed Alzheimer's disease (AD) are still scarce. We report neurohistopathological and biochemical analyses using antibodies against tau and amyloid β (Aβ) pathology.

Methods: Thirty elderly AD patients and 43 age-matched controls with or without deposition of amyloid plaques (AP) were analyzed by immunohistochemistry.

The Vitamin A Derivative All-Trans Retinoic Acid Repairs Amyloid-β-Induced Double-Strand Breaks in Neural Cells and in the Murine Neocortex.

The amyloid-β peptide or Aβ is the key player in the amyloid-cascade hypothesis of Alzheimer's disease. Aβ appears to trigger cell death but also production of double-strand breaks (DSBs) in aging and Alzheimer's disease. All-trans retinoic acid (RA), a derivative of vitamin A, was already known for its neuroprotective effects against the amyloid cascade.

A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease.

The postsynaptic density protein PSD-95 is a major element of synapses. PSD-95 is involved in aging, Alzheimer's disease (AD) and numerous psychiatric disorders. However, contradictory data about PSD-95 expression in aging and AD have been reported.

Pathological reorganization of NMDA receptors subunits and postsynaptic protein PSD-95 distribution in Alzheimer's disease.

In Alzheimer's disease (AD), synaptic alterations play a major role and are often correlated with cognitive changes. In order to better understand synaptic modifications, we compared alterations in NMDA receptors and postsynaptic protein PSD-95 expression in the entorhinal cortex (EC) and frontal cortex (FC; area 9) of AD and control brains. We combined immunohistochemical and image analysis methods to quantify on consecutive sections the distribution of PSD-95 and NMDA receptors GluN1, GluN2A and GluN2B in EC and FC from 25 AD and control cases.

Comparison of frailty of primary neurons, embryonic, and aging mouse cortical layers.

Superficial layers I to III of the human cerebral cortex are more vulnerable toward Aβ peptides than deep layers V to VI in aging. Three models of layers were used to investigate this pattern of frailty. First, primary neurons from E14 and E17 embryonic murine cortices, corresponding respectively to future deep and superficial layers, were treated either with Aβ(1-42), okadaic acid, or kainic acid.

Maladaptive exploratory behavior and neuropathology of the PS-1 P117L Alzheimer transgenic mice.

Patients with the early-onset Alzheimer's disease P117L mutation in the presenilin-1 gene (PS-1) present pathological hallmarks in the hippocampus, the frontal cortex and the basal ganglia. In the present work we determined by immunohistochemistry which brain regions were injured in the transgenic PS-1 P117L mice, in comparison to their littermates, the B6D2 mice. Furthermore, as these regions are involved in novelty detection, we investigated the behavior of these mice in tests for object and place novelty recognition.

Increased postsynaptic density protein-95 expression in the frontal cortex of aged cognitively impaired rats.

In the present work we studied synaptic protein concentrations in relation to behavioral performance. Long-Evans rats, aged 22-23 months, were classified for individual expression of place memory in the Morris water maze, in reference to young adults. Two main subgroups of aged rats were established: the Aged cognitively Unimpaired (AU) had search accuracy within the range (percent of time in training sector within mean ± 2 SEM) of young rats and the Aged cognitively Impaired (AI) rats had search accuracy below this range.

Differential damage in the frontal cortex with aging, sporadic and familial Alzheimer's disease.

In order to understand relationships between executive and structural deficits in the frontal cortex of patients within normal aging or Alzheimer's disease, we studied frontal pathological changes in young and old controls compared to cases with sporadic (AD) or familial Alzheimer's disease (FAD). We performed a semi-automatic computer assisted analysis of the distribution of beta-amyloid (Abeta) deposits revealed by Abeta immunostaining as well as of neurofibrillary tangles (NFT) revealed by Gallyas silver staining in Brodman areas 10 (frontal polar), 12 (ventro-infero-median) and 24 (anterior cingular), using tissue samples from 5 FAD, 6 sporadic AD and 10 control brains. We also performed densitometric measurements of glial fibrillary acidic protein, principal compound of intermediate filaments of astrocytes, and of phosphorylated neurofilament H and M epitopes in areas 10 and 24.

The presenilin-1 familial Alzheimer's disease mutation P117L decreases neuronal differentiation of embryonic murine neural progenitor cells.

The presenilin-1 gene is mutated in early-onset familial Alzheimer's disease. The mutation Pro117Leu is implicated in a very severe form of the disease, with an onset of less than 30 years. The consequences of this mutation on neurogenesis in the hippocampus of adult transgenic mice have already been studied in situ.

Contribution of neural networks to Alzheimer disease's progression.

The neuropathology of Alzheimer disease is characterized by senile plaques, neurofibrillary tangles and cell death. These hallmarks develop according to the differential vulnerability of brain networks, senile plaques accumulating preferentially in the associative cortical areas and neurofibrillary tangles in the entorhinal cortex and the hippocampus. We suggest that the main aetiological hypotheses such as the beta-amyloid cascade hypothesis or its variant, the synaptic beta-amyloid hypothesis, will have to consider neural networks not just as targets of degenerative processes but also as contributors of the disease's progression and of its phenotype.

Differential changes in synaptic proteins in the Alzheimer frontal cortex with marked increase in PSD-95 postsynaptic protein.

We investigated how synaptic plasticity is related to the neurodegeneration process in the human dorsolateral prefrontal cortex. Pre- and postsynaptic proteins of Brodmann's area 9 from patients with Alzheimer's disease (AD) and age-matched controls were quantified by immunohistochemical methods and Western blots. The main finding was a significant increase in the expression of postsynaptic density protein PSD-95 in AD brains, revealed on both sections and immunoblots, while the expression of spinophilin, associated to spines, remained quantitatively unchanged despite qualitative changes with age and disease.

Postsynaptic density protein PSD-95 expression in Alzheimer's disease and okadaic acid induced neuritic retraction.

In order to understand how plasticity is related to neurodegeneration, we studied synaptic proteins with quantitative immunohistochemistry in the entorhinal cortex from Alzheimer patients and age-matched controls. We observed a significant decrease in presynaptic synaptophysin and an increase in postsynaptic density protein PSD-95, positively correlated with beta amyloid and phosphorylated Tau proteins in Alzheimer cases. Furthermore, Alzheimer-like neuritic retraction was generated in okadaic acid (OA) treated SH-SY5Y neuroblastoma cells with no decrease in PSD-95 expression.

Transcription regulator LMO4 interferes with neuritogenesis in human SH-SY5Y neuroblastoma cells.

LMO4 is a transcription regulator interacting with proteins involved, among else, in tumorigenesis. Its function in the nervous system, and particularly in the adult nervous system, has however still to be elucidated. We decided to modify its expression in a neuronal model, human SH-SY5Y neuroblastoma cells, by permanent transfection of sense or anti-sense Lmo4 cDNAs.

Tau and neurofilaments in a family with frontotemporal dementia unlinked to chromosome 17q21-22.

A Swiss frontotemporal dementia (FTD) kindred with extrapyramidal-like features and without motor neuron disease shows a brain pathology with ubiquitin-positive but tau-negative inclusions. Tau and neurofilament modifications are now studied here in three recently deceased family members. No major and specific decrease of tau was observed as described by others in, e.